BreatheTV Episode 26

Aerosol Delivery Methods | A Webinar with Rob DiBlasi, RRT-NPS, FAARC

Transcript

Jeff Maglin: It’s now my pleasure to introduce our speaker, Rob DiBlasi. Rob currently is the Research and QI Manager in Respiratory Therapy, Principal Investigator at Seattle Children’s Research Institute in Seattle, Washington. He is a registered Respiratory Therapist, Neonatal/Pediatric Specialist and a fellow of the American Association of Respiratory Care. Rob has more than 20 years of respiratory bedside experience and close to 20 years in respiratory research. He has authored eight textbook chapters, 31 published articles, and 60 abstracts in respiratory care, and has received 12 grants for his research. His special interests include invasive and noninvasive ventilation and drug delivery in neonates and pediatrics.
Rob is a frequently invited presenter at national, regional, and state respiratory and medical conferences both in the United States and internationally. He has been awarded on four separate occasions for his work, and in 2012 was named the AARC Neonatal/Pediatric Specialty practitioner of the year. I will now hand the controls over to Rob.

Rob DiBlasi: Jeff, thank you for the wonderful introduction and I want to thank Vapotherm especially because we wouldn’t be able to have these opportunities to present to all of you especially during respiratory care week on some of these topics that we’re also interested in. If we didn’t have people like you that are providing these lectures, then folks I think would obviously have to go search the literature themselves or try to find information the best way possible, so I’d like to thank you and thank industry for allowing us to have these opportunities. I would also like to take a little bit of time to thank all of the respiratory therapists and the people that support respiratory therapists whether you are nurses or physicians and say Happy Respiratory Care Week from sunny Seattle.

I wish I could say it was sunny Seattle but we have had the most beautiful fall over here but the weather has changed and now it’s a little bit rainy. I’m here to talk with all of you today and discuss the topic of aerosol delivery during neonatal noninvasive, pediatric noninvasive ventilation and we’ll even touch on some of the larger pediatric patients because I know that in the children’s hospital setting we take care of a lot of these patients that could be a big baby like me. We’ll review all of the different options for aerosol delivery. I will disclose that I have received some funding in the past from Mallinckrodt Medical and also from Draeger Medical for research and speaking on our area and as well as United Therapeutics.

They provided us with some great grants to test a number of hypotheses related to drug delivery with different mechanical ventilators and different positions within the circuit. So thankfully they have done a great job in providing us some of the funds. Aerogen Pharma, I hope and I’m super excited to share some of our data from Aerogen Pharma. They’ve been working on a breath-synchronized vibrating mesh nebulizer that can be integrated into a nasal airway interface so that we could potentially obviate the need for potentially injurious and inflammatory invasive mechanical ventilation. If we have a little bit of time, I hope to share some of our results with you towards the end.

The objectives of this presentation are to actually move through and begin to have discussions about how aerosol delivery is different between pediatric patients. When I say pediatric patients, I mean I’m trying to include neonates, I’m trying to include smaller pediatric patients, and the large pediatric patients that are obviously adult sized. We’ll talk about differences in medication delivery between those different groups, we’re going to talk about clinical and bench data related to aerosol drug delivery. Whenever possible, if we don’t have good, definitive, clinical research to support aerosol delivery, then we absolutely have to turn to our bench models. Luckily, we are very graced now and we are very fortunate nowadays to have 3D printed anatomic airway models which are very similar to those of the airways of babies and adults to describe how much of the drug is actually being deposited in the upper airways versus in the actual lung model, which we use for filter tests.

So we’ll talk about some of our research related to aerosol delivery to that end. Then we’ll talk about how best we can deliver aerosolized drug during invasive ventilation, during conventional and high frequency oscillatory ventilation. I bet there’s a lot of people out there that are wondering, “Can I give aerosolized drug to a pre-term baby and expect that I’m going to get the same drug delivery as an adult? Does the position of where I place that nebulizer have any impact on the drug delivery overall? What if we give the drug and there’s a proximal flow sensor in line which most of our neonatal ventilators have proximal flow sensors? How do we navigate that issue? How do we mitigate the risk?”

We’ll talk about aerosol drug delivery during noninvasive ventilation. I can say that I know there have been babies that have been supported invasively to give nitric oxide, to give Heliox, to give aerosolized drugs when they probably could have been extubated and supported with high flow Nasal CPAP or NIPPV. We know now that there is an inherent risk with providing invasive ventilation longer than we really need to, and so we want to get the kids off the ventilator earlier and support them with high flow or Nasal CPAP or NIPPV. We’re going to talk about the best way to provide drugs in those cases. Keep in mind that there are novel approaches to and novel drugs that people want to be able to give to babies. You may say, “Well, in my NICU, I never give any drugs to babies or in my PICU you don’t really give that many drugs outside of albuterol.”

But there are novel drugs that are coming along that people want to be able to research and they want to be able to use during noninvasive ventilation. We’re going to talk about some of the ways that we can optimize drug delivery with neonatal noninvasive pediatric noninvasive as well as invasive mechanical ventilation. Let’s take a step forward and advance to the next slide. Oh, there we go. Let’s talk about how drug is actually able to be delivered to babies. If we look at this scan right here it shows a small part of the upper airway of an infant and then it shows a bunch of radiolabeled airways going down into the lung. I think it’s important to realize that drug delivery in small infants is very different from adults. There’s a tremendous amount of drug particles that are lost in the upper airway of babies because we know that babies, that airway resistance is proportionally higher when we consider the lung resistance than it is with adults or larger pediatric patients.

Because of that, the upper airway resistance accounts for about two thirds of that total respiratory system resistance, and we know that babies are going to have low pulmonary deposition because of that. But also we know that they have a itty bitty airways, we know that the airways are much smaller, and so for those large particles they may not get down into the lung. It’s especially important that we try to use nebulizers that are going to provide drugs within the respirable particle range. Some may argue that that’s one to seven micrometers or one to five micrometers. In order to get optimal deposition, we may need to select nebulizers that have that output. But until now the majority of the nebulizers that have been designed have really been designed for adults, and they may have inconsistent particle size and they may not have the particle size that will fit with every one of your pediatric patients.

Because we know that they have itty bitty airways, we know that they have increased airway resistance. We know that their peak flows are proportionally higher and we know that their inspiratory times are much shorter, and their cycle times are different from ours. When a baby breathes especially when they’re in respiratory distress, there’s a tremendous amount of turbulence and a tremendous amount of impactive drug loss that not only occurs in the upper airway but also occurs in these itty bitty little airways. You ask yourself the question, “How do babies get any drug delivery at all when we consider the nebulizers we use and the fact that they are physiologically so different from all of us?” If you look at the majority of the studies that have been published in the literature, it’s less than 3% of the nominal dose, the dose that you put in the nebulizer that actually reaches the infant lungs. In adults, it’s much larger, it’s like 10 to 58% because they don’t have these short transit times, they don’t have the airway resistance, they don’t have the low tidal volume and all of that so they get more of the drug. Are babies actually able to get that drug? That’s the question. If we look at all of the available data that’s out there, we have to be very careful as respiratory therapist, as nurses, as doctors, and explore the evidence with a very careful eye.

Because the majority of the evidence that exists, again, has been in bench models or it’s been in human studies that have evaluated radiolabeled isotopes using a gamma camera where all of the drug that’s put into a nebulizer has a small amount of radioactivity that’s placed into that nebulizer. It attaches the aerosol particle and the aerosol’s administered and then we’re able to determine based on what was put in how much of it actually made it into the lung. If we look at those studies where patients were supported that were spontaneously breathing, we know that in the majority of the studies that have been conducted in these smaller infants and in these pediatric patients, that only 0.3 to 1.5%t of the nominal dose placed in the nebulizer reaches lungs.

I the best of those studies, about 2% actually makes it into the lung. In adult studies, obviously, we’ve demonstrated that 8 to 22% of long deposition can be realized when we’re using these radiolabeled isotopes. Are the days of using radiolabeled isotopes to determine how much drugs actually got into the lung gone? No, but it’s very difficult to enroll pediatric patients into those studies because most parents don’t want to expose their kids to radiation albeit the amount of radiation that they experience is probably similar to a six-hour flight at 10,000 feet when you’re up on an airplane. The radiation dose is super low, in fact, it’s lower than an x-ray. But it’s tough to enroll patients into those studies so whenever possible today we’re going to talk about the aerosol deposition for lung model studies versus actual studies that are done in humans but there are fewer of those studies being done.

You may think, “Well, in infants who have these itty bitty airways and these short eye times and they’re not able to hold their breath or coordinate with any type of nebulizer, that they’re not getting any drug at all, so maybe we shouldn’t be doing it.” But that’s not really the case. If you look at the nebulizers output by different Jet nebulizers of small volume nebs that we’ve traditionally used for the last 20, 30, 40 years, you can see that the output is quite high. However, in infants they get a very small amount of that drug down into their lung. As you increase your patient size and your patient age, you get more of that drug. Proportionally more of that drug is delivered to the lung. You may think that aerosol delivery is better for adults than it is for infants but that’s not the case.

If we actually take the percent lung deposition and we compare that against their weight and we normalize that based on their body weight … I’m just going to move this one over here. What we show based on the long deposition is that between infants and larger pediatric patients, the lung delivery, if we reference it to weight, is actually similar between the groups. This is the total absolute delivered lung deposition and we see that with infants, pediatrics, and adults or larger pediatric patients it increases. But then we divide that by the weight, we get similar lung deposition across all. It’s important to realize that it really is weight based and we can reference this based on their weight. Sorry, I’m having a little technical difficulty over here advancing the slide.

There we go, all right. What are the different devices that are typically used, and I think this is super important because we need to understand how well the drug is going to be delivered with all the different devices we use. Not only to deliver the drug but also to integrate that drug and that delivery system within the system that these babies are being supported with or these patients are being supported with. So the delivery options are spontaneous breathing, we can bag it through the ET-tube, we can give it in-line during mechanical ventilation, we can give it in-line during noninvasive ventilation. But the question that arises is, “Well, what device should we be using?” Should we be using a pMDI with a spacer? Is there potential that this can add that space to the system?

Should we be using Jet nebulizers which we know add flow to the system? That makes it difficult to trigger certain devices, but also it may increase the amount of in the respiratory pressure, it may increase the amount of tidal volume that’s being delivered to the patient. Shall we used ultrasonic or vibrating mesh nebulizers to provide these rugs? We’ll move through all of that today and we’ll talk about how safely these devices can be integrated with all of the delivery options that we may use. It’s important to realize that in children, we may have a kid on high-flow nasal cannula one minute and then the next minute they’re on BiPAP and the next minute they’re on some other form of noninvasive ventilation, and then they’re intubated.

Ask yourself the critical question, “Is it safe to deliver the drug? Are we providing adequate drug delivery between all of these different devices?” The array of devices that kids could be supported with within the ICU, on the floor, I think that’s a critical question. There are a couple of devices that have literally revolutionized how we deliver drugs to pediatric patients, and so the different drugs that we would provide to these kids will review a lot of those here as we go through the presentation. But the majority of the drugs that we provide to a pediatric institution is going to be bronchodilators, bronchodilators and steroids. I want to shout out to these two companies, Monaghan Medical and also Aerogen because they literally have revolutionized how we give drugs.

No longer do we have to give Jet nebulizers to all pediatric patients to provide bronchodilators, we now have valve holding chambers that allow patients to breathe in through different valves and exhale so that they are not exhaling particles back into the mean chamber. This has been shown to be very, very effective in providing bronchodilators therapy, but also we have Aeroneb Solo which in my opinion you can argue that it’s a little bit more costly but it’s not adding flow to the system. By not adding flow to the system, we can literally integrate the Aeroneb Solo with any form of invasive or noninvasive ventilation or high-flow nasal cannula therapy. So that has really revolutionized how we give drugs to patients.

I think that what that will do is it will redefine whether certain disease processes require any bronchodilators or not. If you look at a lot of the bronchiolitis research that’s out there, most of those studies have demonstrated that there’s no real clinical effect related to giving bronchodilators but the majority of those studies that were done early on looked at using Jet nebulizers. I think we need to sciences and iterative process, we need to go back and we need to constantly reassess and reevaluate and determine, “Well, are we getting better drug deposition with these pMDIs or spacers and is there potential that Jet nebulizer is providing more drugs than we realize? And so is there a clinical effect? We don’t know.

Basically, I think that if we go back and we look at all the specific age-related guidelines for use of aerosol delivery types, we can reference the good work that was done by Arian Ruben from the AARC Clinical Practice Guidelines, and determined that a lot of these early studies have been able to provide us with a lot of good definitive data and knowledge on how best to support babies and how to provide these aerosolized treatments. If we look at the different age-specific recommendations, it’s been shown that maybe we give a small-volume nebulizer or we give a mask or a hood to provide the drug. Maybe we provide it with a mask, we know that in pediatric patients that are not able to coordinate with the mouthpiece and plug their nose and have guided deep breaths with a mouthpiece, then the mask is the only option we really have.

There’s a pMDI with valve holding chamber which is a relatively new player in the grand scheme of things because people for years thought that you can’t give an inhaler to a baby. Obviously, babies are not going coordinate and take those deep breaths, and so people thought that because adults are able to coordinate and take deep breaths, they are not going to get the drug deposition in children that they would get with adults but that’s not the case. Now we have these valve holding chambers, they can take as few as three to five breaths to clear the chamber and get the drug delivery they need. Other things that we can look at is dry-powder inhaler. Certain drugs use a dry-powder inhaler, MDI, but we would never use an MDI without a spacer, right?

We agree that we would never use an MDI without a valve holding chamber, that’s the right thing to do. But then there’s also a lot of new devices out there, breath-actuated MDIs. Most babies, most children are not able to actuate these. The breath-actuated nebulizers, we talk about the BAN, the breath-actuated nebulizer. There’s a whole host of other drugs out there and other delivery systems that may be easily triggered but there’s not a lot of good data out there to support this in pediatric patients per se. I think we need to evaluate the clinical controversies that exist around aerosol delivery and that’s why I’m here today, and so people … I remember back when I was a new respiratory therapist, there was a nurse that said in these bronchiolitis patients, “Get in there and give that treatment when that baby’s crying, when they’re most upset, because they’re taking the biggest tidal volume possible and they’re going to get better drug deposition as a result of that.”

Maybe some of you have heard this in the past but I have always had my reservations about this because when babies are crying obviously they’re not breathing as quickly but also they’re bearing down, they’re taking these super fast inspiratory efforts at these high picking inspiratory flows and this potential that you may not get the drug delivery that you require in this case. There have been studies that have, and this is more of a lung model study that has a value added or implemented integrated spontaneously breathing respiratory parameters in the lung model for awake babies and asleep babies. They literally went in and measured the respiratory rate and the respiratory tidal volumes in babies that were awake and asleep.

And then they applied Salbutamol or some bronchodilator in the lung model and determined that in those babies that were awake, there was significantly lesser drug delivery than those … I’m sorry, yeah, less drug delivery than those that were asleep. Now I think obviously that was about 74% greater in the sleeping infant model than it was during the asleep model, and I think that that really speaks to the fact that a sleeping baby is a good baby if you’re going to give them a nebulizer treatment. If you can’t get a baby to sleep and they’re awake and they’re pissed, then maybe you hand that baby over to the parent and the parent can pacify that baby so that they’re able to take the treatment effectively.

How do we give the treatment? That’s the question and are there differences between pMDI with spacer versus Jet nebulizer, and what are those differences between screaming, poor mask seal, not screaming with a good mask seal. I think that this is probably one of the most interesting aerosol studies in pediatrics to be published in the last 20 years. This is actually one of the few remaining studies using using radiolabeled isotopes where investigators took the drug that was in the canister of the pMDI as well as in the fill volume or the unit dose of the albuterol. They radiolabeled it and then they took a camera and they actually scanned the drug delivery and so these black dots represent how much of the drug is actually being delivered to the upper airways versus into the lungs.

You can see as we move along there’s more drug delivery, so let me explain this slide though. This right here represents a toddler with a non-tight fitting mask, so this is with an MDI with a spacer and then a non-tight fitting mask with a Jet nebulizer. There’s a lot of information we can gain and glean from this in that babies who do not have a tight fitting mask, that could be blow-by, all right? Maybe you have a mask and you’re doing blow-by, the majority of the aerosol particles are going to the atmosphere. They’re not making it into the lungs, a lot of them are making it into the upper airways and then maybe you get a little bit in the lungs and some of it swallowed into the belly.

Now when you have a tight fitting mask and the baby is screaming, you certainly get a little bit more of that drug delivery into the lungs but we lose a lot of it in the upper airways because of the resistive component. We know that they’re breathing in super fast and those particles are depositing in the upper airways and we also get a bunch that swallowed and that goes into the belly. We don’t get as much, maybe we don’t get any out into the just lung units, we get them into the larger proximal airways. However, if we have a tight fitting mask and these are two subjects per group with a pMDI or spacer, if they’re breathing quietly, we’re able to pacify them like we would if they were sitting with their parents. Then they get so much more drug delivery into the lungs where it is needed.

The interesting thing is people have argued and argued and it’s one of the major clinical controversies in aerosol drug delivery, that pMDI with spacers simply does not provide as much drug as a Jet nebulizer and that’s wrong. I will say, and I’ve got a few slides to prove it, that you can get as much drug delivery as long as you’re using bronchodilators, there’s not a lot of pMDI formulations. As long as you’re using a spacer, you will get the same if not more drug delivery in any patient population as a Jet ventilator, or sorry, a Jet nebulizer. I think that this slide really speaks to the fact that we have to have a tight fitting mask, this is essentially blow-by. They get 0.07% of the drug that’s put in the nebulizer.

You don’t get anything with blow-by but even when you’re screaming, you get a little bit more so we try to pacify the baby and it really doesn’t make a difference between pMDI with spacer versus Jet nebulizer. But we try to make that baby as happy as possible and hand him over to the family, do what you can. But, again, if you can’t get the kid to chill out, and we only have a few options and just keep in mind that blow-by really is not one of those options. Although, I will share some interesting data with you that may actually support it. This is another major clinical controversy, blow-by aerosol treatments are better tolerated and result in better drug delivery than a face mask. Well, we saw that last line, we know that that’s not really the case. You can see here that in this case, there’s a blow-by neb given and most people assume that in babies they breathe through their mouths. We know that babies don’t breathe through their mouth, they actually have preference to breathe through their nose. I think it’s interesting that in both of these pictures right here the family members actually have the wherewithal here to provide a mask treatment but it’s over the mouth, so that kid’s probably not get anything at all. He’s just trucking away and breathing through the nose and these are all pictures that you find online. A lot of family members are a lot of them are considered medical experts at least for their patient and they swear that there’s a clinical response when you provide that aerosol blow-by treatment to the mouth.

We’ve done this for years, I know that I’ve done it a lot myself and I thought that I was given some drug but in reality I probably wasn’t given a whole heck of a lot. Now if you are going to do a blow-by treatment for patients, it’s important to realize that the closer you get to the face, the more the drug you’re actually going to deliver. So ideally it would be best to have it on the face but we know that a lot of kids don’t tolerate that. If you even move it away just a little bit, and we look at drug delivery zero centimeters from the face thus with a mask on the face. Two centimeters and four centimeters away from the face, you can see here that with the PARI, this is the PARI neb, this is the Respironics neb, I believe, yes, B, and then this is the Salter neb that there really is a difference not only when you place it on the face but when you move it away that supports maybe using one of these front loaded masks over some of these other masks here.

You can see here that when you put the PARI right on the face in this one model study that looked at a filter test, that the drug delivery obviously decreases significantly as you move it away from the face. But it really has to do with the mask that you’re using. If you’re going to do blow-by or you are going to give any of these types of treatments, maybe you consider using a front loaded face mask because the aerosol plume is being directed straight in versus being pushed straight up to the top side of the mask. Something to consider if you’re actually going to do these blow-by treatments. Another thing that you consider and I know this seems like way too much work, but there are folks that have evaluated aerosol delivery using radiolabeled isotopes in 14 wheezy infants.

They actually demonstrated that you can get similar drug deposition between a hood, so this is kind of a hood type of set up, with an aerosol tubing coming through as you would get with using a mask. If there was that kid in particular that really needed those nebulizer treatments, then maybe we would consider a hood. But how many kids do you know that have significant airway disease that may need those nebulizers? Well, maybe not now but there are new drugs, again as I mentioned before, that are coming and they’re being introduced to the market. We need to maybe think about how to deliver drugs appropriately using these different setups. The nebulizer position, this is another clinical controversy, the nebulizer position has no effect on drug delivery and should always be placed back in the humidifier in all ventilated pediatric patients.

I think that a large part of the United States right now is placing the nebulizer in those patients that require nebulized therapy especially continuous, they’re placing them back on the dry side of the humidifier. But I’m here to tell you that maybe that’s not how we should be doing it in all of our patients. Spontaneously breathing infants with a face mask. There’s been studies as I mentioned before that there’s no significant difference in the percent of lung deposition using radiolabeled isotopes between pMDI with spacer and nebulizer. But in intubated mechanically ventilated subjects, it’s actually been shown that a pMDI with spacer may result in greater drug delivery. Keep in mind that in these studies there’s a tremendous amount of intersubject variability, it’s tough to do clinical studies like this in ventilated patients.

But again this just goes to show that in intubated subjects, if you can make it work, a Jet nebulizer may be as good as a vibrating mesh nebulizer, at least in animal studies and some of the infant studies as well. There has been a couple of seminal studies that have come along over the last 10 years that have described aerosol drug delivery between all of these different locations using different types of nebulizers, and both pediatric and adult bench studies have looked at these filters after they were met after albuterol was being nebulized. The vibrating mesh nebulizer, for years we have done that and in fact and the Aerogen company said, “Put it as close to the patient as possible.”

But what we haven’t really taken into consideration is the fact that, that may not work well for pediatric, larger pediatric patients, but it will for infants. What is the effect of bias flow as well? Because we’ve got bias flow coming through this system and depending on the ventilator it may be a low bias flow of two liters a minute or it could be upwards of six or eight liters a minute. What happens when that aerosol plume is being produced here? Is it directed to the patient during inhalation or is it kicked off to the expiratory valve during exhalation? That’s the question, how much of the drug are we getting? Does the device make a difference? Does the position make a difference?

I know that Aryan and all and Jim Fink and those folks have done a lot of really good work in the past. I remember reviewing this paper for the Respiratory Care Journal and wrote an editorial on it. What they showed is that the vibrating mesh nebulizer truly does provide two, three, four fold greater drug delivery than a Jet nebulizer. I think with the Jet nebulizer, obviously, you complicate things a little bit because you have to run that at six or eight liters minute and you put that inline during mechanical ventilation. That really makes it so that you can’t, babies especially can’t trigger the mechanical ventilator. When you place it at the Y, they demonstrated with adults that you don’t get as much drug delivery with a vibrating mesh as when you place it back at the humidifier. That makes total sense.

Because in adults, there’s a much larger tidal volume that’s being delivered to the patients, so if there’s an aerosol flume that’s been created and it’s being dispersed or discharged into the circuit, that circuit acts as a reservoir during exhalation to trap all of those particles so that when we deliver a breath, that tidal volume is typically bigger than the internal volume of the circuit, and so that drug actually makes it to the patient within one breath. In pediatrics, we start to see a little bit of a difference now where when you position it at the Y and the tidal volumes are in the range of 200, well, yeah, you still typically appear to get greater drug delivery when it’s placed back at the humidifier.

However, and obviously it’s greater than the Jet nebulizer but it really does appear to be bias flow dependent as well. Meaning that at lower bias flows you get a slower delve time to allow the circuit to serve as a reservoir to capture a lot of those aerosol particles so that they can be delivered to the patient. Now so based on these studies we know that in adults you get more drug delivery when that nebulizer especially the vibrating mesh placed on the dry side of the humidifier and then pediatrics you start to blur the boundaries there and you start all right. It all has to do with the tidal volume that’s being delivered in proportion to the tidal volume that’s lost in the circuit.

We’ve conducted studies that have actually demonstrated using Treprostinil which is an inhaled pulmonary vasodilator. We had published on this a few years ago where using the arrow neb, if you use a mask you get less than with a ventilator which is weird because in the case, and this is a spontaneously breathing lung model, typically any time you add humidity to a system, you’ve reduced drug delivery because of hygroscopic growth related to the aerosol particles meshing with the water vapor from the humidifiers. But what we demonstrate is that the proximal, when you place that nebulizer closer to the patient between the Y and that inspiratory circuit, you actually get more drug delivery than placing it back at the humidifier. But we also demonstrated that with high frequency oscillatory ventilation, you sometimes get two to three for greater drug delivery with neonatal and pediatric settings than you do with a doll.

We conducted this study because we wanted to be able to provide aerosolized drug using this inhaled pulmonary vasodilator as an alternative to inhaled nitric oxide. The majority of the babies that we’ve tried to support with this drug in a clinical study, they were being supported by the oscillator. Who would ever think in a million years that with an oscillator who has a super rapid respiratory rate and high turbulence that we would get any drug delivery at all. But we did demonstrate in two separate studies that you could increase aerosol drug deposition. This is another study that we had published in pulmonary circulation using Iloprost which is similar to epoprostenol and we evaluated and tested the hypothesis in drug delivery differences between placing that nebulizer close to the Y and back at the humidifier. Again, we showed that at least in babies and a lung simulator that was specific to babies, when you place that nebulizer proximately, you get two-fold, three-fold greater drug delivery than when you place it at the humidifier. In babies you need to absolutely realize that when you’re producing an aerosol plume, that plume is being created a little cloud that travels down the circuit. It may take five or six breaths when you’re using a tidal volume of 20 to make it to the lung model or to the filter or to the patient. So during that time you get a lot of impactive drug loss that occurs along the circuit. You don’t get as much drug as if you were to place it right there proximal to the patient. I would suggest placing that nebulizer proximal to the patient any time you’re using the infant circuit or you’re dealing with an infant that’s being mechanically ventilated.

With the oscillator we actually show that there was negligible drug delivery when you put it on the dry side of the humidifier. Whereas if you put it close to the patient you actually get three-fold greater drug delivery. I think that has a lot to do with the way that the active exhalation occurs with the nebulizer and we may have some drug that’s backing up into the expiratory limb then is redirected to the patient with high frequency oscillatory ventilation. That’s a very complex system but it’s going to know that at least we could potentially give the drug with the oscillator. The one thing I want to point out though is that most neonatal mechanical ventilators nowadays use proximal hot wire flow sensors or some type of flow sensor at the airway.

If you’re giving a drug and it is before that proximal flow sensor, you definitely run the risk of shutting a ventilator down or you run the risk of, if you’re volume guarantee, of under-ventilating the patient. I think it’s important to realize at that point that maybe you need to put the ventilator or the nebulizer closer to the patient after the flow sensor or just get rid of the flow sensor in general if it’s an intermittent treatment. We have mitigation strategies where you get rid of the flow sensor or put them in a pediatric mode for certain ventilators and allow the treatment to occur back at the ventilator in those cases. Keep that in mind, understand what you’re ventilator’s capable of, understand how it interacts with nebulizers, look at the ops manual and determine the best way to get that treatment.

If we look at our job then for continuous nebulizers that we provide, this is how we will provide it with infants, this is how we will provide it with kids and adult. So any time you’re on that larger circuit, we’ll put the nebulizer here but in infants we’ll put it here and we’ll remove the proximal flow sensors. Let’s jump into noninvasive ventilation at this point and let’s talk a little bit about how we want to be able to support children and support babies noninvasively. I don’t know how all of you are experiencing noninvasive ventilation at your institution right now but I will say that it’s about, in the NICU, it’s about 70/30 meaning 70% of the babies that are being supported are done so with noninvasive ventilation at least for the majority of their hospital course.

And now there’s some kids that are being placed on invasive mechanical ventilation. In the PICU, we always strive to support our patients noninvasively whether it’s with high flow or refusing the BiPAP type of devices. We know that invasive mechanical ventilation is closely associated with injury and information and we try to avoid that whenever we can. But also we try to get the patient off the mechanical ventilation whenever we can. We shouldn’t keep patients on the ventilator solely for the purpose of delivering certain types of therapy whether it’s nitric oxide or Heliox or aerosolized drugs. That’s the paradigm shift that we’ve observed over the last several years where the majority of the kids are going to be supported by Nasal CPAP or BiPAP.

So you will see more and more aerosolized drugs being delivered to these kids because there’s a lot of exciting things that are happening. Now, there are a significant number of patients that are being supported by BiPAP that obviously would benefit from a course of bronchodilator therapy. We’re trying to avoid intubation in this case. We try to provide bronchodilators to alleviate bronchiospasm. We’ll give other inhaled steroids potentially to reduce airway inflammation. There are certainly plenty of patients that we know that we support and try to avoid mucous accumulation, we try to break up the secretions like we do in CF patients and we see a lot of kids on BiPAP as a result of that.

There are certainly plenty of drugs out there now that have been designed and developed to provide pulmonary blood flow improvements and it’s a less expensive alternative and we know that people want to be able to use those and treat infection improve compliance. So many of these aerosols are typically, as I mentioned before, not given with non-invasive support, they’ll keep kids intubated to provide these drugs to them. Which I think is probably a poor idea at this point and we know that in the past gas powered nebulizers, jet nebulizers add flow to the system that can increase tidal volume, increase pressure, and definitely reduce the patient’s ability to trigger the ventilator.

We know that there could be some hazards as a result of this, we’ve got masks hooked up to patient’s face, we’ve got high-flow nasal cannula, what is the effect of that drug getting on the face or getting in the eyes? We don’t really know, so these are all unknown questions. Many patients are, as I mentioned before, kept on these therapies or we are switching their noninvasive support level or noninvasive support to be able to provide the therapy in a better way. These are some of the diseases at least in the neonatal period where we would provide some form of inhaled specialty gas as well as some inhaled aerosolized drugs. Especially, in respiratory distress syndrome, these babies that are being born prematurely, there’s a huge effort right now to support them with inhaled surfactant.

We’re going to talk about that a bunch, talk about some raw research related to that. Meconium aspiration, people are interested because these babies have persistence of fetal circulation, they’re interested in providing Prostacyclins, maybe Iloprost, Treprostinil. Some folks have discussed Flolan, Perflubron, Partial Liquid Lung Ventilation. All of these are extremely experimental and congenital congenital diaphragmatic hernia, inhale nitric oxide is a big one. Not too many inhaled drugs in most cases but again primary pulmonary hypertension same thing, lots of experimental aerosolized drugs. Pneumonia, antibiotics, hypertonic saline, things that we can break up the secretions. BPD, there’s a strong signal to support using inhaled corticosteroids and especially bronchodilators.

We’ve seen great response in bronchodilation in those kids with BPD, and then in congenital cardiac anomalies there’s lots of different drugs that we consider experimental. Why don’t we give drugs, inhaled drugs, with noninvasive support? Well, I think that it depends on where you put the nebulizer, it depends on the device you’re using, but in the majority of the devices that we use to provide CPAP, the prongs are placed in the airway. If we look at these fluid dynamics models, we can see that there is a lot of business going on in providing inhaled gases. During exhalation, you’ve got all these different separate flow pathways with this infinite flow generator which we use for years, the air life flow generator. Similar type of situation where we’ve got different jets of gas coming in and then reversal of these little jet nozzles coming in.

How could we possibly deliver any drug to a patient considering all of these little low pressure and high pressure fronts within these systems? That’s a question, do we lose it all and what about with Bubble CPAP? We’ve got Bubble CPAP which provides small amplitude high frequency pressure oscillations. Is it possible that maybe we’re not delivering any drug in those cases? What about high-flow nasal cannula? We know that with high flow that’s a leaky system, right? We’re providing a monophasic flow going down into the airways, you’re occupying only about 50% of the nasal airway opening. Are we losing a bunch of that drug and are these nebulizers that are producing that aerosol, is it possible that if we have a wonderfully I:E ratio, that drug, the majority of it’s being lost into the atmosphere. Or could it be with high flow that we’re producing aerosol within this nasopharyngeal that’s based and it’s acting much like a spacer would provide with regard to harboring those aerosols. So that with the onset of the next breath they’re getting a bunch of that aerosol down into their lung, we just don’t know. We simply do not know, but we do know that with high-flow nasal cannula, it is very difficult to remove a patient from high flow to be able to provide a treatment to them. We’re going to spend a lot of time on that today discussing it. What are some of the challenges associated with noninvasive delivery of inhaled medications? As I mentioned before, it really has to do with the device that you’re using, the respiratory support device you’re using, has to do with the setting, it has to do with how you’re breathing. It has to do with, you know, especially if you’re considering Heliox and nitric oxide, what is the likelihood that we’re going to produce a toxic gas that’s going to be breathed in?

Where are we putting that device? Are we going to be removing the device to give the drug? How does humidity impact the drug delivery? Because with a heated high-flow nasal cannula system we know that gas is 100% humidified. If we put a nebulizer in line with that system, we know that humidity, right off the bat, is going to reduce drug delivery by 50%. I can’t emphasize that enough. What about food accumulation? What if it hits a cannula that’s not heated? Where it’s not heated to the optimal level and we have more fluid going by there. Is that going to result in significant fluid accumulation that could be transmitted to the infant’s nasopharyngeal airway and that could create an obstruction because we have too much fluid that’s being kicked off into the nasopharynx? How do these jet nebulizers impact additional flow? How does that affect triggering of the device? What about the airway interface, does the nasal mask versus the nasal prongs, does that provide more drug delivery in this case? We don’t know, a lot of those questions are unanswered. Infant CPAP, if we look at some of the reasons why we would give nebulizer treatments to them, we know that infants may require intermittent aerosolized medication delivery with nasal CPAP or even noninvasive IMV. There’s been a couple of great studies that have been published recently in the last three or four years where some bowling colleagues, they actually looked at drug delivery with the fluidic flip CPAP device which is essentially noninvasive IMV at lower pressures.

They show that it provided lower drug mass and high-flow nasal cannula and Bubble CPAP. That’s more of a cyclic positive pressure delivery system and they demonstrate it in this lung model with a filter that there are no differences between the nebulizer circuit positions for high flow. Meaning with this Fisher & Paykel system, there was no difference between placing a proximal for the patient versus back prior to the humidifier. The differences were really not different between high flow and CPAP but during Bubble CPAP they actually demonstrated that placing that nebulizer prior to the humidifier resulted in greater drug delivery than placed proximal to the patient. That confuses things a little bit but you need to realize with Bubble CPAP that’s a continuous flow system and it’s typically a higher flow rate than you would observe with an invasive mechanical ventilation or invasive mechanical ventilator.

Finally, in colleagues actually showed greater delivery of radiolabeled isotopes by a Jet nebulizer placed 32 centimeters away from the nasal CPAP prongs than when placed back at the humidifier. They support using it proximal but the drug delivery was super small in those cases, and so placing the nebulizer closer to the humidifier resulted in more drug delivery being delivered to the actual circuit and into the nasal prongs. These are the different positions right here and this is the aerosol deposition, and as you look, a lot of drugs left behind in the nebulizer in this case when you’re using it with this infant flow system and these are the different positions. This is position B close to the patient and then back to the humidifier and you can see here that when you’re placing it close to the humidifier you get lots of drug loss in the tubing and less to the patient. So something to keep in mind.

For years, we never thought in a million years that we could actually provide drug delivery to patients who are being supported by the trilogy or being supported by the BiPAP ST or any of those devices that we would typically use for noninvasive support that had a single circuit limb. Obviously, these are we’re talking about larger infants now. Therapy doesn’t need to be stopped, sometimes we intubate to give continuous bronchodilators or we always question whether or not we can do this because of the fact that we have this little leak valve that we may lose a lot of that drug. I think it has everything to do with where you position that nebulizer. There are studies out there folks that have shown that in humans aerosolized drug delivery during noninvasive ventilation is actually 30% greater than when you know an idea is being used.

Those are pretty early studies ever done in cystic fibrosis patients. If you have a patient who has respiratory distress, we used to do IPPB all the time where we give treatments under pressure. It may be beneficial to place patients on NIV to provide these aerosolize drugs. But the one thing I can mention is that you need to place that nebulizer as close as possible to the patient. If you have the ability to put the leak valve prior to the nebulizer, we have demonstrated that you can increase the drug delivery two-fold. So with that being said, we worry that if you put the nebulizer back at the humidifier with BiPAP, that a lot of that drug gets lost in the circuit and we’re breathing back and forth through that circuit. But also we have this big old leak and so a lot of that drug is being directed to the atmosphere and less of it is going to the patients. If you put the aerosolized medication after the leak in these single circuit limbs, then you’re bound to get more of that drug delivery. We show this actually in the Respiratory Care Journal a few years ago, position one, that’s with the Aeroneb, we placed it at the humidifier. You’re getting negligible drug delivery, but then even if you place it after the leak or as close to the patient as possible, then you’ll still be able to get a little bit more drug delivery. But if you integrate that nebulizer, and I know that there’s this NIVO nebulizer on the market but you get it close to the mask, then there’s no risk.

A lot of people are using this to improve or increase the drug delivery to patients especially in those asthmatics that may need that drug immediately and we’re trying to avoid intubation. Their safety risk is associated with delivering aerosol with noninvasive ventilation. There can be fluid accumulation if you’re providing with high-flow nasal cannula. We’ve seen babies that have had air solved delivery or albuterol burns to the face because it drools down, it goes into nasopharynx, it comes down on the face. The expiratory valve on mechanical ventilators, if you’re giving them inline can accumulate a bunch of debris and a bunch of stuff that could affect the performance of the mechanical ventilation to increase the airway resistance and increase the expiratory resistance of the valve. So keep that in mind and make sure that you filter the drug before you give it in line during mechanical ventilation. But also with Bubbles CPAP we’re seeing more that we’re giving some of these drugs and that some of the drug is being kicked off to the expiratory valve and that could add to excessive fluid accumulation in the expiratory valve of the Bubbles CPAP. So you may create a choke point so that the flow going to baby could be much higher, and the Bubble CPAP level could be much higher than what we think based on their depth. It’s important to measure the pressures of the airway in those cases. Now we get down to the point where we’re talking about providing aerosolized drug delivery to babies or children that are being supported by high-flow nasal cannula.

I will say that this is probably the single most controversial aerosol delivery discussion that we’re having right now in the clinical practice because no one really knows what to do. Because high-flow nasal cannula therapy is super complicated, right, we’re using different flow rates, we’re providing potentially drug through the system or removing a high-flow nasal cannula or placing a mask over the high-flow nasal cannula. It’s a different beast than it is with noninvasive, which is inclusive or with invasive which is inclusive and it’s pretty straightforward in those cases. But because you’re providing optimal humidity in these cases, we right off the bat we affect aerosol delivery but also it’s a noninclusive system. Do we entrain more Reminiac at these lower flows? What device should we use? Should we be using a Jet nebulizer that you set a flow but then that flow will add to the high flow if you’re integrating in the system?

There’s so many questions that have come up and we really don’t have any good answers. There have been some good bench studies that are out there, none of these studies have really evaluated drug delivery using a 3D anatomic airway model. Some of these have been bench tests that have been conducted with a spontaneously breathing model but they have improvised nasopharyngeal airways. I know that Dr. Fink in RE they’ve done a lot of seminal work related to this. But they’ve done it with a Fisher & Paykel system, and then with the F&P system you can put that nebulizer prior to the unifier, you can put it close to the patient. There’s lots of different ways that you can deliver this drug and with this particular system that prongs are typically, the diameter of the prongs is much larger.

There’s potential that you can get more of than a drug in there, but we really don’t know. There haven’t been good human studies to determine whether or even getting any drug with high-flow nasal cannula at this point. What they’ve demonstrated is that with 100% oxygen, maybe we’re getting somewhere in the range of 10% of the drug at these lower flow rates or 2% at these higher flow rates. One thing that we know for sure is that you increase the flow rate during high-flow nasal cannula regardless of the system, you reduce the delivery because of the impactive drug losses that occur in those cases and the higher humidity output that’s occurring in these cases. You can argue with that by applying a little bit of Heliox, maybe you increase the drug delivery that’s going to the patient.

But I think that is especially important at these higher flow rates but again Heliox is an expensive drug and we may not be using that. In larger pediatric patients or adult sized patients with oxygen versus Heliox, we see here that 27% at 10 liters may potentially be delivered to a lung simulator or to an adult. As we increase the flow rate, lesser of that drug, significantly less of that drug is being delivered to the patient. In those cases that you have a patient that’s on high-flow nasal cannula, you may consider reducing that flow rate significantly at least during the treatment as tolerated. It appears here that a little bit more of that drug may be delivered to the patient if you’re using Heliox.

We’ve done studies actually that using the older … What was it? The Fisher & Paykel system, the older system and we compared with actual 3D printed nasal airway models between infants and that was a newborn infant and a pediatric size infant with a 3D anatomic airway model with spontaneous breathing. We actually looked between no Heliox and Heliox gases with a face mask, and then at one flow setting I think it was eight liters a minute. We demonstrated that actually you get lower drug delivery based on the absolute, this is the absolute mask delivered to a filter. You get lower drug delivery with Heliox because it’s a slippery gas and it’s escaping to the nasal fairings. We maintained a 50% inclusion in this 3D anatomic airway model and showed that with high flow you only get about half of the drug delivery is what you would get with a face mask and Heliox certainly doesn’t help.

In pediatric models, obviously, we’re going to get more of that in a toddler or a small child and it’s still only about half the drug delivery. I think it really does depend on the device that you’re using, and so if you’re using the F&P system, then always remember that you’re probably going to get half the drug delivery you would get with a face mask treatment as you would get with a high-flow nasal cannula. But again that was only at one fixed flow rate. Other studies have evaluated in a non-human primate model the effects of drug delivery and I think that this is probably one of the most interesting studies that we’ve seen in a while where Reminiac and a number of colleagues have used radiolabeled isotopes both in a saint model and in the human or the non-human primate macaque model.

What they did is they placed the vibrating mesh nebulizer on the dry side of the humidifier at two, four, eight liters minute and then they use the Jet nebulizer at six liters a minute in line. And then outside of that, they compared the Jet nebulizer mask alone just placing it on the mouth and then they placed it over the nasal cannula. I know that there are people that probably place their small volume Jet nebulizer or a vibrating mesh nebulizer over the high flow cannula. Because it’s not inclusive, they think that they’re going to get some drug. That may be the case and others have actually demonstrated that there is some clinical effect related to that. But if we look at those radiolabeled isotopes and we look at this mapping and this would be the face, this is eight liters a minute with a Jet nebulizer placed on top of a high-flow nasal cannula.

You could see here that there’s literally no drug that’s being delivered to the lungs, however, there’s a tremendous amount of drug that’s being delivered to the face. I think that has been our experience but others have demonstrated that if they just use more of the drug, they get it down past the cannula and babies can breathe through the nose and get that down into the lung. But you have to make sure that you’re using a cannula that’s half the size of a nasal airway opening. It seems to me that based on these data, that it’s not a great idea to use the Jet nebulizer at eight liters a minute or eight on top of high flow at eight liters a minute as well. This is what it looks like when you put a Jet nebulizer within a circuit, within the high flow circuit.

Nothing being delivered to the lungs and I think that may have to do with the fact that you’re using a bunch of gas to power that jet nebulizer and now you’re adding a bunch of resistance within the cannula. Vibrating mesh nebulizer, at the higher flow rates we see that a lot of the drug gets on the face, maybe a little bit on the throat, some in the belly. But as we reduce the flow rate with the vibrating mesh nebulizer integrated into the high flow circuit as we reduce that flow rate, there’s more laminar flow, less turbulence, and we start to get more of that drug being delivered. If you want to take a nebulizer and place it in series with a high-flow nasal cannula, please consider using lower flow rates as the patient tolerates it. If not, then maybe the kid needs to be taken off.

This one’s to the control here where they actually looked at with an aerosolized Jet nebulizer with a mask in this non-human primate. They demonstrated that you get a lot of facial deposition but at least you get a fair amount that’s going to the lung and that’s not too much different from what you would get with the nebulizer being integrated into the circuit. This again was done with F&P Optiflow system. There hasn’t been a lot of work that’s been done with the Vapotherm 2000i however I’ve spoken with many people and they still continue to integrate the nebulizer in line. Obviously, the previous study did it back at the humidifier with the Vapotherm that you have to do a proximal to the patient.

So folks have evaluated both and this was one bench study to keep in mind, one bench study looking at different flow rates that are commonly used with adults, infants, pediatric patients, and they demonstrated that there wasn’t a lot of drug delivery with the Vapotherm system. However, I think we need to reiterate those and redo those studies because based on that one study, folks feel as though there’s a lot of fluid accumulation that may build up in that AAA adapter that connects the nebulizer to the circuit. Maybe the fact that Vapotherm firm uses much smaller cannula, that could impact drug delivery to the subject. However, there are some abstracts out there and there’s some data out there that actually shows that patients may actually have similar responses to getting the aerosol with the Vapotherm as they would with mechanical ventilation or they would with spontaneous breathing.

There are some abstracts out there and I know that I’m excited to work with Vapotherm over the next couple of years to determine and quantify how much drug delivery is being placed into the lungs of babies as well as adults, we just don’t know. We don’t really know at this point but what we have done and I think that this will be interesting for a lot of you out there that are using the HVNI system with the precision flow, that’s a major question is how should we be delivering this drug? What should we do at this point? We have a white paper that’s going to be published here in the next few weeks that a lot of you can refer to, to understand what different people are using in different settings,

This was a survey that was started by our Taft and started by Mark Kolnsberg and it was a very well thought out survey that included exclusively HVNI users and folks that were using the Vapotherm system because we wanted to know and identify and do the formative research to understand what are you doing right now to deliver aerosol in the case of patients who are using HVNI therapy. Basically, what we came home with his our findings indicate a variety of practice methods that may effectively deliver aerosolized medications during HVNI. We found that some clinicians will actually switch from the HVNI system and go over to an F&P system, but I don’t know if that’s absolutely necessary.

These are the characteristics for the phone interview for the study that we conducted and these are the different credentials that put the majority of the people that were involved in the survey were respiratory therapists, we had a bunch of physicians and these areas that they worked mostly in the critical care arenas. Of course we had a great representation of folks from all over the United States. These are some of the pros and cons of the patient interfaces in children from that internet survey. I know that we did a lot with adults as well but I’m just going to focus on the children. This was their experience with that AAA adapter which I showed in the previous slides. Their concern was that there were some rain out or maybe inconvenient. They talk about the ease of use, they think that it was super useful in this case, it was well tolerated by the patient.

These are all the pros and these are some of the cons and I know that some people felt like because it’s not heated, that there was some rain out. A lot of folks obviously are giving mouthpiece treatments to some of these children and a lot of these adults they are able to coordinate. I think that, that would be an amazing area of research to understand how patients that are receiving high-low nasal cannula may benefit from getting a mouthpiece treatment because obviously their mouth isn’t occupied and so what is the effect of a face mask with and without the cannula? That’s another thing especially for those kids that are not able to tolerate the mouthpiece.

The majority of the responses were very helpful in understanding how drug is being delivered with HVNI, and we know that there’s a lot of controversy about the methods of delivering drugs with HVNI. But the majority of the physicians that we interviewed by telephone all stated that they obtained expected clinical responses when their RT staff provided aerosol therapy to patients receiving HVNI. I think that that really carries a lot of weight, obviously, it’s not easy to assess or evaluate bronchodilator response in these patients. It is very difficult but if you can see that the heart rate’s going up and you can see that the respiratory rate is coming down, the breath sounds are improving. Then maybe they are getting a lot of that drug whether it’s from a face mask placed over the HVNI which is a smaller cannula or being integrated in line during that treatment.

What we determine with intermittent treatments, the majority, 78% of all the people that we polled, they indicated that they did not pause the HVNI therapy while performing intermittent aerosol therapy. When treating children, the cannula were used most often, so about 46% of the time they gave the treatment through the system. And 31% of them actually used a face mask and then 8% percent used a mouthpiece, and then there was a small group of people that actually switched to another high-flow nasal cannula system. The respondents who actually paused the HVNI during the single dose of aerosol, they did so because there was concerns with medication delivery. They weren’t sure if the drug was getting there or there was rain out, or they didn’t have a vibrating mesh nebulizer and they wanted to try to prevent excessive flow from entering the system when that neb was being used.

The internet survey indicated overall that the most commonly used nebulizer when pausing HVNI was in Jet neb but the most common nebulizer that was being used when it was integrated into the system was going to be the vibrating mesh nebulizer and I think that’s interesting. If we have any type of information for you, if you’re using HVNI, based on our survey and based on some of the data that exists out there, if clinically tolerated HNVI therapy may be paused for aerosol therapy. Again, with preference for a mouthpiece used with a pMDI or a breath-actuated nebulizer, but the duration of that probably should be kept at a minimum. We know that a lot of these patients tolerate this treatment quite well, some of them may rely on an oral leak to flush the nasopharynx and eliminate rebreathing CO2.

When we can’t pause HVNI therapy, then the flow on the high flow should be reduced as low as possible. We showed in a number of slides that at the lower flow rates, we get less turbulent flow, less deposition in the upper airways and potentially the circuit. So try to reduce the flow rate whenever possible. Then if we can’t pause it using a vibrating mesh to deliver, the aerosol may be considered. Keep that in mind, care must be exercised when using a Jet nebulizer because we don’t want to add additional flow and increase the pressure that’s being provided by that high flow system.

In summary, with intermittent treatments, when HVNI therapy cannot be paused because patients can’t clinically tolerate interrupting HVNI, higher target doses may be required to accomplish a therapeutic goal. Albuterol is pretty cheap in the grand scheme of things and so if you’re not getting the clinical response you want, then you can increase the dose or you can increase the length of the therapy and I think that you could get a similar clinical benefit. But I think that this really opens up a whole new line of research where we need to evaluate how well are we getting drugs in those patients who we remove the cannula and give it with a face mask? How well are we delivering the drug when we put the mask over the high-flow nasal cannula and then when we integrate it into the system.

I think that we can’t look at just one study and assume that we’re not getting the treatment we think we may be getting. With continuous nebulizer treatments, it’s been shown based on the survey that around 50% of all the children that are getting some form of bronchodilator or some aerosolized treatment, the majority of them are continuous. In children we get more continuous therapy being delivered, and so I think the majority of the internet survey respondents, I think that 83% they do not stop high flow therapy to administer aerosolized therapy. All 17% do, so there’s a lot of folks out there that obviously see the value in using high flow. We know that with high flow you provide some back pressure in the lung, we know that with high flow you provide rinsing of the anatomic dead space.

That may or may not be improved and more efficient with HVNI, and so it’s difficult to stop this therapy to provide the aerosolized drug and we really don’t know what the best thing to do is. A number of facilities indicate that they use the Aerogen nebulizer connected to a syringe pump. I know that we have done that in the past but currently we will actually switch someone to noninvasive ventilation to provide this therapy if we’re going to do it continuously. But we would be willing to attempt to try to do this with the Vapotherm system if we had a little more data. If the patient requires continuous aerosol, like I mentioned, we place them either on … We have never placed them on another high flow system but I know folks that do because there’s wider board tubing going down through the nasal channel or like I mentioned we may go to noninvasive ventilation.

But I wouldn’t necessarily go with what we’re saying here, I would just realize that if you’re going to be using this with the HVNI system that you may need to use a little bit more drugs, but you could probably get a similar effect. You need to take into consideration that there is some condensate that could be produced and you have to make sure that the lines are cleared and you’re not bolusing patients measly with the drug or with the humidity. Obviously, I would try to avoid as much as possible using a Jet nebulizer in line with HVNI. I would switch to the vibrating mesh nebulizer at whatever cost. Unless you have a larger patient and they’re on 40, 50 liters a minute of high flow, then you can easily integrate a Jet nebulizer into that system.

Just realize that you should probably back down on your flow as much as possible with the HVNI system. Then I always consider, you know, mask and mouthpiece are an option but we just don’t really know how much of that drug is getting down there in those cases. In order to optimize aerosol deposition and deliver a long dose of medication and reduce impactive drug losses with HVNI setting, make sure you wean that as low as possible. Again, if you’re not getting the clinical effect you need, then you should consider switching to some other form noninvasive ventilation. I realize that I do not have a lot of time left, however, I wanted to provide you with a little bit of primer on some of the interesting research we’re doing now with aerosolized affecting.

But these are our guidelines right here, these are guidelines that our hospital related to providing aerosolized drug delivery with vibrating mesh. This is exclusive to vibrating mesh. I will provide you with all of these slides as needed. These are some of the reported drug deposition levels with high-flow nasal cannula. As much as possible if you can provide it prior to the humidifier, there are folks that think that the larger particles are being filtered off the humidifier and you optimize drug delivery that way, or proximal to the patient as much as possible. But do not place that treatment over the nasal prongs, that’s what we say at our institution but there are some folks that will use a face mask over the high- flow.

But based on the findings of Reminiac, we demonstrated that or they demonstrated that there’s really no drug delivery. Keep in mind that if you’re using high flow in combination with a nebulizer treatment, it may cause excessive fluid. These are all of our different suggestions for where you place the drug and how you mitigate some of the issues related to drug delivery between all the different devices. These are the different devices that we would give drugs. This is a flow diagram right here which I’m glad to send off to all of you that goes through the scenarios of invasive ventilation high flow bubble or BiPAP bubble and spontaneous breathing. These are different ways to navigate how to give the treatment based on the ventilators that we use.

This is the future and we worry now because we’re going to see a lot of patients nowadays that are going to require some form of noninvasive support in combination with aerosolized drugs. One of the big aerosolized drugs that we’re going to see in the next 10 years is going to be surfactant delivery. We know that in pre-term babies, they have fluid filled lungs, they have [inaudible 01:15:03], they’re sick, they require surfactant replacement. We know that in order to provide surfactant replacement therapy to these patients, we either have to intubate them, give them the surfactant, subject them to short-term mechanical ventilation which we know causes injury and inflammation, or we place them on CPAP while we wait for them to declare themselves as having high respiratory stress and being swift, fast, and efficient based on FIO2>40 and high work of breathing.

But what if we could intervene and find common ground between providing aerosolized surfactant and never having to go on to a mechanical ventilator ever again to be able to provide that drug. That’s part of the work that I’ve been focused on over the last few years. There’s many different ways to do it in a patient who’s being supported by noninvasive ventilation. Folks have demonstrated that you can give it through the intra-amniotic fluid, you can give it to patients that are presenting at the premium. And who have not taken their first breath, you just instill a bolus through the upper airway and they breathe it in, LMEs, CPAP, we could give it through a thin calf or in those babies that are being supported by nasal CPAP. And then or we could give it aerosolized through the system.

There’s a lot of work that’s being done right now to determine how can we provide this aerosol, this aerosolized surfactant during noninvasive ventilation. So of those studies that have been done, the majority of them have use nebulizers that are producing aerosol throughout the whole respiratory cycle. Not just during inhalation, but the whole respiratory cycle. So of those studies, they’ve shown clinical response but they’ve had to use four or five times the dose in order to provide this clinical response similar to what we would give with instilled surfactant. There’s been a number of studies that have been conducted evaluating surfactant delivery with noninvasive ventilation.

These of those clinical studies and each one of them have shown that there is some improvement in oxygenation, some improvement in ventilation of reducing the need for invasive mechanical ventilation. But again they had to use four times, three times the dose because these nebulizers are giving it throughout the whole respiratory cycle. These have been some of the limitations in the past, gas jet, gas-powered nebulizers Jet nebulizers just simply are not very effective. They don’t produce the aerosol that we need, now with vibrating mesh nebulizers that’s a little bit of a different story. I know that we have tried to vaporize stuff using vaporized different types of drugs, using the Vapotherm HVNI system.

There’s a number of different options that we may explore later on. I know that Lucinactant and different types of aerosol or … What am I trying to say? Different types of surfactant that are not animal derived have been evaluated and assessed using different types of noninvasive support. They really haven’t been able to show that there’s a huge benefit in babies, and so there is another study that’s out there now that folks are evaluating using a binky, using a pacifier, where they take this long catheter and they place it through the pacifier and they’re evaluating aerosolized drug delivery and prevention of intubation in babies using this nebulizer here that’s made by Monaghan Medical.

I think this one is particularly interesting because they’re injecting this aerosolized surfactant to the retro fairing so that babies when they exhale there’s always a fresh bolus of drug that’s able to be inhaled. They’re using this with nasal CPAP and having some pretty dramatic results. Other studies are comparing between the Aeroneb just being placed in line during Bubble CPAP. Keep in mind with Bubble CPAP and other forms of CPAP, there’s high bias flow going through the system. You lose a lot of that drug and it doesn’t really get to the patient. It may be super expensive to deliver aerosol to these patients but I’ve been working with Aerogen Pharma over the last few years and we have worked with them to develop a miniature-sized vibrating mesh nebulizer that’s breath synchronized and can be integrated into the nasal prongs. It’s breath synchronized based on flow or based on using graseby capsule to provide aerosolized surfactant only during inhalation. The studies that we’ve done so far are fairly compelling in that they … Oh, sorry, are fairly compelling in that compared with babies or rabbits that are being supported invasively and having drug dribbled down through direct installation with a catheter, we’ve demonstrated that we can get a better clinical response with aerosol. Because I think it’s more evenly distributed throughout the lungs fields and I can’t … Let me just try to show you this really quickly without the laser pointer on. This is the little nebulizer here and this is a little lung that’s being inflated.

You can see that the drug’s only being applied just prior to the onset of inhalation so a lot of that drug is being delivered to the patient’s airways. We’ve done some studies with rabbits and we’re finding more and more that this may be the way to go and there may be several advantages obviously over giving it through direct installation through the tube. We showed lower bradycardia, we showed less desaturation, less peak inspiratory pressure when delivering this, and we’ve used electrical impedance tomography to determine that the distribution of gas, volume or gas in the lungs is preferable. These are some of our preliminary data showing that after we lavash patient’s or subject’s lungs of these rabbits, we take all the surfactant out with salt water and then we apply the nebulizer that in time there’s a pretty significant increase in the PAO tube.

And then these are subjects that were supported by nasal CPAP after being excavated following a lavash. Let me show that when the nebulizer is initiated, the PH levels are actually much higher with aerosol surfactant and the PACO2 levels are much higher. I think that is pretty exciting to know that we’re moving toward better options that will allow breath synchronized aerosol delivery during nasal CPAP using surfactant. By using breathe synchronized, we don’t have to continuously provide this drug throughout the whole respiratory cycle. We know that as many as 50 to 60% of all pre-term infants need to be reintubated after they’ve been excavated and that may be due to the fact that they need more surfactant being delivered.

But every time that we need to do that, we now put them at risk because we have to intubate them and put them on a ventilator for those purposes. So that will conclude my presentation for today. I thank you all for joining me and hopefully you have a little bit of a better understanding of how aerosolized drugs can be delivered in these cases. Thank you.